Valaciclovir tablets containing colloidal silicon dioxide

ABSTRACT

A tablet comprising at least 50% w/w valaciclovir and 0.05 to 3% w/w colloidal silicon dioxide in which the valaciclovir is present within granules of the tablets and the silicon dioxide, a lubricant and a microcrystalline cellulose filler are present extragranularly has excellent hardness and friability properties while still maintaining lubrication of the tablet granules.

This application is a 371 of PCT/GB96/00111 filed Jan. 19, 1996.

This invention relates to a tablet of the antiviral drug valaciclovir.

The compound 9- (2-hydroxyethoxy)methyl!guanine, otherwise known asacyclovir possesses potent antiviral activity and is widely used in thetreatment and prophylaxis of viral infections in humans, particularlyinfections caused by the herpes group in humans (see, for example,Schaeffer et al, Nature, 272, 583-585 (1978), UK Patent No. 1523865,U.S. Pat. No. 4,199,574). However, acyclovir is poorly absorbed from thegastrointestinal tract upon oral administration and this lowbioavailability means that multiple high doses or oral drug may need tobe administered, especially for the treatment of less sensitive virusesor infections in order to achieve and maintain effective anti-virallevels in the plasma.

The L-valine ester of acyclovir (2-2-amino-1,6-dihydro-6-oxo-9H-Purin-9yl)methoxy!ethyl L-valinate (hereinreferred to as valaciclovir) has been shown to possess much improvedbioavailability whilst retaining the anti-viral properties of acyclovir.A preferred form of this compound is its hydrochloride salt which isherein referred to as valaciclovir hydrochloride. Valaciclovir and itssalts including the hydrochloride salt are disclosed in U.S. Pat. No.4,957,924 (see particular example 1B), European Patent No. 0308065 (seeparticularly example IB) and Beauchamp et al, Antiviral Chemistry andChemotherapy, 3(3), 157-164 (1992) (see particularly page 162 column 1).Tablets of valaciclovir are also generally disclosed in the U.S. Pat.No. 4,957,924 and European Patent No. 0308065.

During development of a tablet formulation containing a high proportionof valaciclovir, we often encountered difficulties in obtaining tabletsof sufficient hardness and friability for pharmaceutical handling andfor film coating.

If the tablet is too friable, it will chip or break during packaging andtransport. The US Pharmacopoeia (USP) no. 23, 1995, p1981 at monograph1216 requires that pharmaceutical tablets have a friability notexceeding 1%. If the tablet is too soft, it will crumble during,tumbling in the film coating pan.

In the reference manual `Problem Solver` (compiles by FMC Corporation)at pages 8 and 9, the remedies for low tablet hardness are given interalia as increasing the compression force applied to form the tablet, ordecreasing the proportion of lubricant in the tablet formulation.

We tried to increase the hardness and friability of valaciclovir tabletsby increasing the compression force, by decreasing the proportion oflubricant and increasing the proportion of biner, but found in each casethat a sufficiently hard and non-friable tablet could not be produced ina practical way.

Furthermore, cracks were found in some tablets as a result of increasingthe compression force. Additionally, valaciclovir has `adhesive`properties in that it can stick to tablet dies and therefore needs to beefficiently lubricated. It is difficult therefore to reduce theproportion of lubricant without causing the tablets to stick.Furthermore, the disintegration time of the valaciclovir tablet is alsoquite long and therefore any possible solution to the hardness andfriability problem should not have a substantial deleterious effect oneither the disintegration time or lubrication (as measured by theejection force) of the table formulation.

It is therefore an object of the invention to provide a robust tabletformulation of valaciclovir and salts thereof which is capable of beingfilm coated and consistently providing tablets having a friability notexceeding 1%, a hardness of at least 9 kP and an ejection force notexceeding 1000 Newtons (1 kN).

The hardness of the tablet should be such that it not only has anacceptable crushing force (as measured by the kP value), but also thatthe tablet does not break during tumbling.

It is a further preferred object of the invention to provide a robustformulation which is capable of consistently providing tabletssubstantially free of cracks.

We have now found an effective method of overcoming both of the abovefriability and hardness problems which involves the extragranular use ofcolloidal silicon dioxide and microcrystalline cellulose in the tabletformulation.

The Handbook of Pharmaceutical Excipients 1994 at p253-256 does notmention colloidal silicon dioxide as an agent to improve the hardness oftablets. Neither does The Theory and Practice of Industrial Pharmacy(third edition) by Lachman, Lleberman and Kanig, mention colloidalsilicon dioxide for such a use.

Accordingly in a first aspect of the invention there is provided atablet comprising at least about 50% w/w valaciclovir or a salt thereofpresent within the granules of the tablet, a microcrystalline cellulosefiller, a binding agent, a lubricant selected from talc, sodium laurylsulphate and alkaline earth metal stearates, and about 0.05% to about 3%w/w colloidal silicon dioxide, the lubricant, colloidal silicon dioxideand at least a portion of the filler being present extragranularly,wherein the friability of the tablet does not exceed 1%, the hardness isat least 9 kP and the ejection force does not exceed 1000 Newtons.

A tablet of this formulation containing 0.05% to 3% w/w colloidalsilicon dioxide and microcrystalline cellulose is robust, and has asubstantially improved friability and hardness. Furthermore suchimproved properties is achieved while still retaining a satisfactorydisintegration time and lubrication properties, even when theformulation is blended under high shear. An excellent tablet providingacyclovir in a highly bioavailable form is thus provided by virtue ofthe invention.

Preferably the disintegration time of the tablet is not more than about30 minutes, more preferably not more than about 25 minutes, and mostpreferably not more than about 20 minutes.

The ejection force should not be more than about 1000 N, preferably notmore than about 800 N, more preferably still not more than about 500 Nfor tablets compressed at about 10 to 30 kN, preferably 10 to 20 kN.

Valaciclovir or a salt thereof are hereinafter referred to generally asthe `active ingredient` or `drug`.

The 1994 U.S. Pharmacopoeia describes colloidal silicon dioxide (in itsmonograph) as: a submicroscopic fumed silica prepared by the vapourphase hydrolysis of a silica compound.

Preferably the colloidal silicon dioxide is present in amounts of about0.05% to about 1% of the total formulation, more preferably at about0.1% to about 1% w/w, and most preferably about 0.1% to about 0.5% w/w.We have found Aerosil (trade mark) and Cab-o-sil (trade mark) to be verysuitable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3, show X-ray powder diffraction patterns of the product ofexamples 1B and 2B.

The content of drug in the tablet is at least about 50% w/w, preferablyabout 60% w/w to about 90% w/w, more preferably still about 65% w/w toabout 85% w/w and most preferably about 80% w/w/. Preferably the(tapped) bulk density of the drug is about 0.1 to 0.9 g/cc, morepreferably 0.3 to 0.7 g/cc, more preferably still 0.34 to 0.66 g/cc, andmost preferably 0.4 to 0.6 g/cc. Suitably the drug is valaciclovirhydrochloride, preferably being of an anhydrous crystalline formincluding substantially a d-spacing pattern (derived from X-ray powderdiffraction) as follows:

d spacing pattern (in Angstroms):

10.20±0.08, 8.10±0.06, 7.27±0.06, 6.08±0.05, 5.83±0.03, 5.37±0.02,5.23±0.02, 4.89±0.02, 4.42±0.02, 4.06±0.02, 3.71±0.02, 3.39±0.02,3.32±0.02, 2.91±0.01, 2.77±0.02.

Hereinafter by "anhydrous crystalline form" according to the invention,we mean a crystalline form having substantially the same X-ray powderdiffraction pattern as shown in FIGS. 1 to 3, or having substantiallythe same d pattern a defined above.

Preferably the crystal form purity in any such drug lot of anhydrouscrystalline valaciclovir hydrochloride used for valaciclovir tablets isat least 70%, more preferably at least 80%, more preferably still atleast 90% and most preferably at least 95% anhydrous crystallinevalaciclovir hydrochloride (as characterised above).

In an alternative method for measuring crystal form purity, since theanhydrous crystalline form of valaciclovir hydrochloride containssubstantially no water of hydration, the level of other hydrated formsof valaciclovir hydrochloride in any drug lot used for tablets can bemeasured by the water of hydration content. Preferably any such drug lotof anhydrous crystalline, valaciclovir hydrochloride contain no morethan 3% w/w, more preferably no more than 2% w/w, more preferably stillnot more than 1% w/w and most preferably not more than 0.5% w/w water ofhydration.

This water of hydration content is measured by the Keri Fischer methodwhich is well known in the art and is described in the 1990 U.S.Pharmacopoeia at pages 1619-1621, and the European Pharmacopoeia, secondedition (1992), part 2, sixteenth fasicule at v. 3.5.6-1.

The filler is microcrystalline cellulose and is at least partly presentextragranularly, which mitigates stress cracking of the tablet. A tabletformulation of the invention including colloidal silicon dioxide andextragranular microcrystalline cellulose appears to have a synergisticeffect and is particularly good and robust in that tablets ofvalaciclovir can consistently be made to an acceptable hardness withoutintroducing stress cracks even under a high compression force.

According to a preferred aspect of the invention there is provided atablet comprising at least 50% w/w valaciclovir or a salt thereof, abinding agent, a lubricant selected from talc, sodium lauryl sulphateand alkaline earth metal stearates, 0.05 to 3% w/w colloidal silicondioxide, and 3 to 30% of microcrystalline cellulose; wherein thevalaciclovir or salt thereof is present within the granules of thetablet, the lubricant, colloidal silicon dioxide, and at least a portionof microcrystalline cellulose is present extragranularly; wherein thefriability of the tablet does not exceed 1%, the hardness is at least 9kP, and the ejection force does not exceed 1000 N.

Preferably the microcrystalline cellulose (e.g. Avicel) present at 5 to15% w/w, most preferably about 10% w/w. The particle size of themicrocrystalline cellulose is preferably 20 to 300μ, more preferably 30to 200μ, and most preferably 50 to 100μ.

The binding agent serves, for example, to bind the primary and secondaryparticles together and improve tablet hardness. Preferably the bindingagent is present in an amount of about 1% to about 5% w/w, morepreferably at about 2% to about 4% w/w, and is suitably a non-starchbased binder such as methylcellulose or most preferably povidone. Thegrade of povidone is advantageously K30 and most preferably K90.

The binding agent such as the povidone, can be dissolved in thegranulating solvent (such as water) before adding to the drug, butpreferably it is added (at least partly) dry to the drug and otherexcipients and then the granulating solution (such as povidone in water)added.

The lubricant is suitably present in an amount of about 0.1% to about2.0% w/w, preferably about 0.1% to about 1.0% w/w. Although talc orsodium lauryl sulphate are suitable, preferably the lubricant is analkaline earth metal stearate, such as magnesium stearate. The aboveamounts apply to the stearate, and they are ideally present in amount ofat about 0.3% to about 0.6% w/w.

Although valaciclovir is very soluble, especially in its salt form, itis preferable if a disintegrating agent is present in the tabletformulation, suitably in an amount of about 0.5 to about 20% w/w, morepreferably at about 0.5% to 7.0% w/w. The disintegrating agent isadvantageously present within the granules of the tablet and can beadded before or after the binding agent. Clays such as kaolin, bentoniteor veegum (trademark), and celluloses such as microcrystalline celluloseor croscarmellose sodium e.g., Ac-Di-Sol (trademark) maybe used asdisintegrants. Preferably a non-ionic disintegrant such as crospovidoneis used. Preferably, the crospovidone is present at about 0.5% to about7.0% w/w, more preferably about 2 to about 5% w/w, and preferably aportion is present intragranularly.

A further aspect of the invention provides a process for preparing atablet comprising at least about 50% w/w valaciclovir or a salt thereof,a binding agent, microcrystalline cellulose filler, a lubricant selectedfrom talc, sodium lauryl sulphate and alkaline earth metal stearates,and about 0.05 to 3.0% w/w colloidal silicon dioxide, wherein thehardness of the tablet is at least 9 kP, the friability is not more than1%, and the ejection force is not more than 1000 N; said processcomprising forming granules which include valaciclovir or a salt thereofand then blending the lubricant, colloidal silicon dioxide and at leasta portion of the filler with said granules.

Preferably said process comprises forming granules by mixing saidvalaciclovir or salt, optionally a binding agent or a portion thereof,and optionally a portion of the filler; granulating with a granulatingsolution to form granules or dissolving the binding agent or a portionin the granulating solution before adding to valaciclovir; drying thegranules; blending the granules with the lubricant, colloidal silicondioxide, and filler or a portion thereof; and then compressing theblended mixture to form a tablet.

A preferred aspect of the invention provides a process for preparing atablet comprising at least 50% w/w valaciclovir or a salt thereof, abinding agent, a lubricant selected from talc, sodium lauryl sulphateand alkaline earth metal stearates, 0.05 to 3% w/w colloidal silicondioxide and 3 to 30% w/w of microcrystalline cellulose filler; whereinthe hardness of the tablet is at least 9 kP, the friability is not morethan 1%, and the ejection force is not more than 1000 N; said processcomprising forming granules by mixing the valaciclovir or salt, optionalbinding agent or a portion thereof, and optionally a portion ofmicrocrystalline cellulose filler; granulating with a granulatingsolution to form granules or dissolving the binding agent or a portionthereof in the granulating solution before adding to valaciclovir;drying the granules; blending the granules with the lubricant, colloidalsilicon dioxide, and at least a portion of the filler; and thencompressing the blended mixture to form a tablet.

the colloidal silicon dioxide can be first blended with the lubricant,preferably a stearate derivative (e.g. magnesium stearate) beforeblending with the granules or it can be added separately from thelubricant. When the lubricant is a stearate, preferably the ratio orstearate to colloidal silicon dioxide is about 1:1 to 10:1, morepreferable about 1:1 to about 3:1.

The present invention also provides a tablet (as described above) foruse in medical therapy, e.g. in the treatment of a viral disease in ananimal, e.g. a mammal such as a human. The compound is especially usefulfor the treatment of diseases caused by various DNA viruses, such asherpes infections, for example, herpes simlex 1 and 2, varicella zoster,cytomegalovirus, Epstein-Barr viruses or human herpes virus-6 (HHV-6) aswell as diseases caused by hepatitis B. The active compound can also beused for the treatment of papilloma or wart virus infections and, mayfurthermore be administered in combination with other therapeuticagents, for example with zidovudine, to treat retroviral associatedinfections in particular HIV infections.

In addition to its use in human medical therapy, the active compound canbe administered to other animals for treatment of viral diseases, e.g.to other mammals. The present tablet also provides a method for thetreatment of a viral infection, particularly a herpes viral infection,in an animal, e.g. a mammal such as a human, which comprisesadministering to the host one or more tablets of the invention toprovide an effective antiviral amount of the active compound.

The present invention also provides the use of the active compound inthe preparation of a tablet of the invention for the treatment of aviral infection.

A tablet of the invention may be administered by any route appropriateto the condition to be treated, but the preferred route ofadministration is oral. Although tablets generally are included withinthe scope of the invention, for example a dispersible tablet or chewabletablet, preferably the tablet is a swallowable tablet, most preferably afilm-coated swallowable tablet. It will be appreciated however, that thepreferred route may vary with, for example, the condition of therecipient.

For each of the above-indicated utilities and indications the amountsrequired of the active ingredient (as above defined) will depend upon anumber of factors including the severity of the condition to be treatedand the identity of the recipient and will ultimately be at thediscretion of the attendant physician or veterinarian. In generalhowever, for each of these utilities and indications, a suitableeffective dose will be in the range 1 to 150 mg per kilogram bodyweightof recipient per day, preferably in the range 5 to 120 mg per kilogrambodyweight per day (Unless otherwise indicated, all weights of theactive ingredients are calculated with respect to the free basevalaciclovir). The desired dose is preferably presented as one, two,three or four or more sub-doses administered at appropriate intervalsthroughout the day. These sub-doses may be administered in unit dosageforms, for example, containing about 50 to 2000 mg, preferably about250, 500, 1000 or 2000 mg of active ingredients per unit dose form.

The following dosage regimes are given for guidance: treatment of herpessimplex virus types 1 and 2 infection:- total daily dose of about 1 or 2g administered at 500 mg twice a day or 1 g twice a day for 5 to 10days; suppression of herpes simplex virus types 1 and 2 infections:-total daily dose about 250 mg to 1 g for about one to ten years(depending on the patient);

treatment of varicella zoster virus infections (for example shingles):-daily dose about 3 g administered at 1 g three times a day for sevendays; suppression of cytomegalovirus infections:- total daily dose about8 g administered at 2 g 4 times a day. For transplant patients thisdaily dose is administered for three to six months for the period atrisk; and for HIV positive patients said daily dose is administered asusually indicated for improving quality of life, for example for twoyears or more.

Early results now indicate that valaciclovir can be used in theeffective suppression of recurrent genital herpes at a once daily doseof from about 200 mg to about 1000 mg for an effective treatment period.The most likely daily dosages are 250 mg, 500 mg or 1000 mg.

Valaciclovir hydrochloride was made as described below:

EXAMPLE 1

A. 2- (2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxy!ethyl-N-(benzyloxy)!-L-valinate

CBZ-L-value (170 g) was dissolved in dimethylformamide (DMF) (750 ml)and cooled. A cold solution of N,N-dicyclohexyl-carbodiimide (DCC)(156.7 g) in DMF (266 ml) was added and stirred with cooling. Acyclovir(10.1 g) was added in a single portion, and then 4-(dimethylamino)pyridine (9.4 g) was added while maintaining cooling. The mixture wasstirred cold overnight. A white precipitate of the by-product was thenremoved by filtration. The filtrate was reduced in volume by vacuumdistillation and the concentrate treated with water (663 ml) then heatedto 70° C. The suspension was cooled to 20° C., filtered and the solidwashed with water.

The damp, crude material was then purified by recrystallisation fromdenatured alcohol (1.2 liters) to afford the title compound as a dampwhite crystalline solid (281.5 g).

B. 2- (2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy!ethyl-L-valinatehydrochloride

2- (2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy!ethyl-N-(benzyloxy)carbonyl!-L-valinate (175 g) was charged to aqueous denaturedalcohol (335 ml/795 ml) and heated to reflux. The solution was thencooled to 40° C. The suspension was treated with 5% palladium on carboncatalyst (35 g wet weight 50% wet with water) then formic acid (30.6 mlof 90% w/w) added over 1 hour. The reaction mixture was stirred for afurther 1 hour then a second charge of formic acid made (19.5 ml) andthe mixture filtered to remove the catalyst. The filter cake was washedwith denatured alcohol and the combined filtrates were treated withconcentrated hydrochlorid acid (33.7 ml) and the resultant mixture wasconcentrated by vacuum distillation.

Acetone (1295 ml) was then added over 15 minutes and the suspensionstirred for 1 hour before filtering off the product. The solid was thenslurried with acetone (circa. 530 ml), refiltered and dried at 60° C. invacuo to give the title compound (1123 g:81.6%).

A 15 g sample of this material was combined with denatured alcohol(circa. 7 ml), to moisten and was heated with agitation at 60° C.overnight in a closed flask to avoid loss of alcohol and maintain thedampness of the mixture. The mixture was then dried at 60° C. in vacuoto afford the product as the desired morphic form.

Physical Data:

Karl Fischer value: 0.9% w/w water.

The X-ray powder diffraction patterns of the product of example 1B areshown in FIG. 1 of the accompanying drawings.

The d spacings and further X-ray diffraction data are shown in Table

                  TABLE 1    ______________________________________                              d Spacing           Angle     Peak     pattern Error in                                             I/Imax    Peak No:           (degrees) (counts) (Å) d (± Å)                                             (%)    ______________________________________    1      3.56      680      24.8    0.5    24    2      8.62      1151     10.25   0.08   39    3      9.42      87       9.38    0.07   3    4      10.86     1438     8.14    0.06   49    5      12.10     835      7.31    0.06   28    6      13.22     198      6.69    0.05   6    7      14.49     2172     6.11    0.05   75    8      15.12     455      5.85    0.03   15    9      15.90     352      5.57    0.02   12    10     16.45     1969     5.38    0.02   68    11     16.90     744      5.24    0.02   25    12     17.33     119      5.11    0.02   4    13     18.12     1013     4.89    0.02   35    14     22.71     1429     4.43    0.02   49    15     20.55     256      4.32    0.02   8    16     21.21     370      4.19    0.02   12    17     21.83     753      4.07    0.02   26    18     22.71     95       3.91    0.02   3    19     23.95     2893     3.71    0.02   100    20     25.10     171      3.54    0.02   5    21     26.21     1784     3.40    0.02   61    22     26.89     428      3.31    0.02   14    23     27.08     373      3.29    0.02   12    24     28.02     158      3.18    0.02   5    25     28.27     161      3.15    0.02   5    26     28.91     391      3.09    0.02   13    27     29.68     191      3.01    0.02   6    28     30.55     502      2.92    0.02   17    29     31.34     110      2.85    0.02   3    30     31.58     98       2.83    0.02   3    31     32.13     597      2.78    0.02   20    32     32.96     260      2.72    0.02   8    33     33.99     344      2.64    0.02   11    34     34.38     374      2.61    0.02   12    35     35.12     141      2.55    0.02   4    36     36.78     408      2.44    0.02   14    37     38.71     101      2.32    0.02   3    ______________________________________     I/Imax = (peak height/max. peak ht) × 100

The powder sample used to produce the above X-ray diffraction data wasprepared by an equivalent method as the powder sample used to producethe X-ray diffraction data of table 2 (described hereinafter) exceptthat for the above data the following preparation was used to preparethe powder sample.

The sample was prepared by milling 1 g of sample in a plastic cup usingtwo acrylic balls for 5 minutes with a Chemplex Spectromill. The sampleswere then back packed against a glass slide to a depth of 2 mm.

The X-ray diffraction scan was obtained using a Scintag PADVdiffractometer in the step scan mode at 0.02° per step and a 10 secondcount per step. The sample holder was spun at 1 rotation per secondduring the scan. Additional setting as described below.

X-ray generator: 45 kV, 40 mA

Radiation: Copper K alpha radiation

Fixed divergent slit: 1 mm

Incident scatter slit: 2 mm

Diffracted scatter slit: 0.5 mm

Receiving slit: 0.3 mm

Goniometer radius: 235 mm

Detector: Scintillation with a graphite monochromator.

The peak intensities are reported as absolute counts of the peak top.The intensity units on the X-ray diffraction plot are counts/sec. Theabsolute counts=counts/sec×count time=counts/sec×10 sec. The peakintensities in the table have been corrected for background and copper Kalpha II X-ray wavelength contribution.

EXAMPLE 2

A. 2- (2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxylethyl-N-(benzyloxy)carbonyl!-L-valinate

CBZ-L-valine (167 g) was dissolved in dimethylformamide (DMF) (750 ml)and cooled to 0.5° C. A cold solution of N,N-dicyclohexylcarbodiimide(DCC) (153.5 g) in DMF (266 ml) was added followed by acyclovir (111.7g) in a single portion. 4(Dimethylamino)pyridine (9.4 g) was then addedand the mixture stirred cold overnight. A white precipitate of theby-product was then removed by filtration. The solvent was partiallyremoved by vacuum distillation and the concentrate treated with water(663 ml) then heated to 70° C. The suspension was cooled to 20° C.,filtered and the solid washed with water.

The damp, crude material was then purified by recrystallisation fromdenatured alcohol (1.2 liters) to afford the title compound as a dampwhite crystalline solid (215.3 g).

B. 2- (2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxylethyl-L-valinatehydrochloride

2- (2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy!ethyl-N-(benzyloxy)carbonyl!-L-valinate (200 g) was charged to aqueous denaturedalcohol (382 ml/908 ml) and heated to reflux to dissolve solids. Thesolution was cooled to 40° C. The suspension was treated with a 50% w/wpaste of 5% palladium on carbon catalyst and water (40 g) then formicacid (96% w/w:32.8 ml) added over 1 hour. The reaction mixture wasstirred for a further 1 hour then a second charge of formic acid made(20.88 ml) and the mixture filtered to remove the catalyst. The filtratewas treated with concentrated hydrochloric acid (38.56 ml) and theresultant mixture was concentrated under vacuum.

Acetone (1480 ml) was then added over 15 minutes and the suspensionstirred for 1 hour before filtering off the product. The solid was thenslurried with acetone (ca. 500 ml), refiltered and dried at 60° C. invacuo to give the title compound (137.75 g:87.6%).

A 10 g sample of this material was combined with denatured alcohol (3.5ml), heated at 60° C. for several hours and the solvent then removed invacuo to afford the product as the desired morphic form.

Crystal From Purity: the sample of example 2(B) contained above 90% ofthe anhydrous crystalline form valaciclovir.

The X-ray powder diffraction patterns of the product of example 2(B) areshown in FIGS. 2 and 3 of the accompanying drawings in which:

FIG. 2 is a linear plot X-ray diffractogram; and

FIG. 3 is a square root plot X-ray diffractogram.

The d spacings and further X-ray diffraction data are shown in Table

                  TABLE 2    ______________________________________                                 d Spacing              Angle    Peak      pattern                                        I/Imax    Peak No:  (degrees)                       (counts)  (Å)                                        (%)    ______________________________________    1         3.62     2673      24.40  35    2         7.21     119       12.26  2    3         8.64     1910      10.22  25    4         9.43     180       9.37   2    5         10.86    2652      8.14   35    6         12.12    734       7.30   10    7         13.24    615       6.68   8    8         13.77    106       6.42   1    9         14.50    2333      6.11   31    10        15.14    635       5.85   8    11        15.89    511       5.57   7    12        16.44    2652      5.39   35    13        16.90    1267      5.24   17    14        17.33    475       5.11   6    15        18.13    1648      4.89   22    16        20.05    2172      4.43   28    17        20.56    640       4.32   8    18        21.20    1096      4.19   14    19        21.78    2034      4.08   27    20        21.90    1384      4.06   18    21        22.66    729       3.92   10    22        23.94    7621      3.71   100    23        24.39    1624      3.65   21    24        25.11    967       3.54   13    25        25.86    2460      3.44   32    26        26.21    5127      3.40   67    27        26.82    1892      3.32   25    28        26.89    1927      3.31   25    29        27.19    1429      3.28   19    30        27.99    1156      3.18   15    31        28.35    1076      3.15   14    32        28.87    1722      3.09   23    33        28.94    1529      3.08   20    34        29.62    1274      3.01   17    35        30.56    1673      2.92   22    36        31.30    999       2.86   13    37        32.25    2570      2.77   34    38        33.04    1376      2.71   18    39        34.00    1806      2.63   24    40        34.45    1225      2.60   16    41        35.13    1149      2.55   15    42        36.77    1600      2.44   21    43        38.01    576       2.37   8    44        38.76    729       2.32   10    45        39.52    524       2.28   7    46        40.70    751       2.22   10    47        41.28    870       2.19   11    48        41.88    686       2.16   9    49        42.47    718       2.13   9    50        43.40    548       2.08   7    51        44.53    729       2.03   10    ______________________________________

The diffraction patterns of the product of example 2B were generated ona Phillips PW1800 Automatic X-ray Powder Diffractometer using a scan of2 to 45 2- with step intervals of 0.02 degrees and an integration timeof 4 seconds per step.

Generator settings: 40 KV, 45 mA, Cu alpha 1,2 wavelengths: 1.54060,1.54439 Å; Step size, sample time: 0.020 deg, 4.00 s, 0,005 deg/s;monochromator used: yes; divergence slit: automatic (irradiated samplelength: 10.0 mm); peak angle range: 2.000-45.000 deg; range in Dspacing: 44.1372-2.01289 Å; peak position criterion: top of smootheddata; cryst peak width range: 0.00-2.00 deg; minimum peak significance:0.75 maximum intensity: 7621 cts, 1905.3 cps.

The powder sample was prepared as follows:

A 1 gram portion of valaciclovir hydrochloride was transferred to aRetsch 10 ml polystyrol container ref 31-762 containing 2 acrylic ballsref 26-253 and was then ground to a very fine powder using a Retsch MM2miser mill set at 100% power for five minutes. The ground powder wasback loaded into a Philips PW1811/10 sample holder which had been placedinverted on a perfectly smooth surface (e.g. that afforded by a glassplate or a highly polished metal sheet). The powder was then packed intothe holder and further powder added and packed until the holder wasfull. A Philips PW 1811 00 bottom plate was then clamped into the holderand the entire assembly was then inverted before removing theglass/metal plate in an upwards direction to reveal the smooth samplesurface which was flush with that of the holder.

The invention is illustrated below in the following examples and theproperties of the tablets show in table 3 hereafter.

    __________________________________________________________________________            Example            3          4          5          6          7            mg/ kg/    mg/ kg/    mg/ kg/    mg/ kg/    mg/ kg/    Ingredients            tablet                Batch                    w/w                       tablet                           Batch                               w/w                                  tablet                                      Batch                                          w/w                                             tablet                                                 Batch                                                     w/w                                                        tablet                                                            Batch                                                                w/w    __________________________________________________________________________    Core.sup.1 (intra    granular):    valaciclovir            576.5                0.9916                    82.0                       576.5                           0.9916                               82.8                                  576.5                                      0.9916                                          82.3                                             576.5                                                 0.9973                                                     82.3                                                        576.5                                                            0.9973                                                                82.0    hydrochloride*.sup.2    microcrystalline            70.0                0.1204                    10.1                       70.0                           0.1204                               10.0                                  70.0                                      0.1204                                          10.0                                             --  --  -- --  --  --    cellulose (Avicel    PH101)    crossprodione            28.0                0.04816                    4.0                       28.0                           0.04816                               4.0                                  28.0                                      0.04816                                          4.0                                             14.0                                                 0.02422                                                     2.0                                                        14.0                                                            0.02422                                                                2.0    povidone K30    povidone K90            22.0                0.03784                    3.1                       22.0                           0.03784                               3.2                                  22.0                                      0.03784                                          3.1                                             22.0                                                 0.03806                                                     3.1                                                        22.0                                                            0.03806                                                                3.1    extragranular:    micro.sup.3 crystalline            --  --  -- --  --  -- --  --  -- 70.0                                                 0.05600                                                     10.0                                                        70.0                                                            0.05600                                                                10.0    cellulose (Avicel    PH101)    crospovidone            --  --  -- --  --  -- --  --  -- 14.0                                                 0.11200                                                     2.0                                                        14.0                                                            0.01120                                                                2.0    collodial silicon            2.0 0.00160                    0.3                       --  --  -- --  --  -- --  --  -- 2.0 0.00160                                                                0.3    dioxide (CAB-O-    SIL M-5 ®)    magnesium            4.0 0.0032                    0.6                       4.0 0.0032                               0.6                                  4.0 0.00320                                          0.6                                             4.0 0.00320                                                     0.6                                                        4.0 0.00320                                                                0.6    sterate    TOTAL   702.5                1.2028                    100.0                       696.5                           1.198                               100.0                                  700.5                                      1.2012                                          100.0                                             700.5                                                 1.12998                                                     100.0                                                        702.5                                                            1.13158                                                                100.0    WEIGHT    __________________________________________________________________________     *Bulk density 0.6 g/cc after 50 taps (anhydrous crystalline form): Karl     Fischer water content = 0.4.     .sup.1 Core weight per batch: 0.5572 kg for examples 3, 4 and 5; 0.4900 k     for examples 6 and 7.     .sup.2 Factor 1.153 = 100     .sup.3 Average particle size about 50

    Example                            8                   9    Ingredients             mg/table   w/w      mg/table   w/w    __________________________________________________________________________    valaciclovir hydrochloride*                            615        65.80    615        65.74    lactose                 205        21.93    205        21.91    microcrystalline.sup.1 cellulose (Avicel PH101)                            75         8.02     75         8.02    (intragranular)    povidone K30            18         19.3     18         1.92    crospovidone (intragranular)                            18         1.93     18         1.92    colloidal silicon dioxide (Aerosil 200)                            0.0        0.0      0.9        0.10    magnesium stearate      3.6        0.39     3.6        0.38    TOTAL WEIGHT            934.6      100.0    935.5      100    __________________________________________________________________________     *bulk density 0.45 g/cc after 50 taps (anhydrous crystalline form)     .sup.1 Average particle size about 50μ.

    Example                            10                  11    Ingredients             mg/table   w/w      mg/table   w/w    __________________________________________________________________________    valaciclovir hydrochloride*                            580        81.01    580        82.60    lactose                 --         --       --         --    microcrystalline cellulose.sup.2 (Avicel PH101)                            70         9.78     --         --    (intragranular)    microcrystalline cellulose                            --         --       70.4       10.03    (extrangranular)    povidone K30            35         4.89     --         --    povidone K90            --         --       21.7       3.09    crosrovidone (intragranular)                            28         3.91     12         1.71    crospovidone (extragranular)                            --         --       14.1       2.01    magnesium stearate      3.0        0.42     4.0        0.57    TOTAL WEIGHT            716        100.0    702.2      100.0    __________________________________________________________________________     *bulk density 0.38 g/cc after 50 taps (anhydrous crystalline form)     .sup.2 Average particle size about 50μ.

The tables of the examples were made as disclosed below.

EXAMPLES 3 TO 7

Step 1. The core ingredients were sifted with a 20 mesh hand screen, andthen blended in an appropriately sized V-shell blender for 10 minutes.

Step 2. The blended powders from Step 1 were then granulated in a 10liter high shear mixer (model-SP1) by adding pure water while mixing.Approximately 11-14% water, w/w of the core ingredients was then addedand the mixture massed for 3 to 41/2 minutes.

Step 3. The granule from Step 2 was dried in a tray (examples 5, 6 and7) or vacuum (examples 3 and 4) drier (model-SP1) at a temperature of50° C. to an acceptable moisture content of approximately 1.0 to 2.0%L.O.D.

Step 4. The remaining ingredients were sifted through a 20 mesh screenand added to the core ingredients of step 3, and then the mixture wassifted using a Comil Model 197 AS fitted with a 0.062" screen.

Step 5. The mixture was then blended in an appropriately sized V-shellblender for 5 minutes.

Step 6. The blended granule from Step 5 was compressed on a Manesty BetaPress fitted with capsule shaped tooling, 18.25 mm×7.14 mm, at acompression weight of approximately 700 mg and a compression force ofabout 14.5 to 18 kN.

Step 7. The tablet can then optionally be film coated by using standardmethods such as using white colour concentrate,methylhydroxypropylcellulose titanium dioxide, polyethylene glycol andpolysorbate.

Hardness (crushing force through the long axis) was measured using a Keyhardness tester, Model HT-300 Friability (percent weight loss after 100,six inch drops) was measured in accordance with the USP no. 23, 1995,p1981 at monograph 1216, using an Erweke friability tester, Model TA-3.Physical properties were measured at comparable compression forces. Thedisintegration time was measured in accordance with the monograph in USP23 (1995) at page 1790.

EXAMPLES 8 AND 9

Step 1. The following ingredients as shown were sifted with a handscreen.

30 Mesh

valaciclovir hydrochloride 5.289 kg

lactose 1.763 kg

microcrystalline Cellulose 0.6450 kg

povidone K30 0.1548 kg

crospovidone 0.1548 kg

60 Mesh

magnesium stearate 0.03096 kg

colloidal silicon dioxide (CSD) 0.002598 kg

Step 2. The 30 mesh sifted ingredients from Step 1 were then blended,excluding the povidone, in a 1 cubic foot V-shell blender for 10minutes.

Step 3. 1.540 kg of SD3A alcohol (ethanol denatured with 5% methanol)was then mixed with 0.6600 kg of purified water and the screenedpovidone, 0.1548 kg, was dissolved in 0.6192 kg of the mixed solvents byhand stirring.

Step 4. The blended powders from Step 2 were than granulated in a 1cubic foot Littleford Lodige mixer by adding the dissolved povidonewhile mixing. 1.315 kg of more mixed solvent was added and the mixturemassed for seven minutes total as shown below.

Ploughs 7 min

Choppers 6.5 min

Step 5. The granule from Step 4 was then dried in a Fluid Bed Dryer(Glatt GPCG5) with an inlet air temperature of 50° C. to any acceptablemoisture content of approximately 1.0 to 3.0% L.O.D.

Step 6. The granule from Step 5 was then sifted using a Fitz Mill ModelM fitted with a 30 mesh screens, with knives forward, operating atmedium speed.

Step 7. The screened magnesium stearate from step 1 was added to thegranule from Step 6 and blended for 5 minutes using the blender fromStep 2. This was labelled as example 10 (2.650 kg).

Step 8. Part of the blended granule from Step 7 was compressed on aManesty Beta Press fitted with oval tooling, 19.1 mm×10.2 mm, at acompression weight of approximately 934.6 mg.

Step 9. The remainder of the lubricated granule 2.650 kg (from Step 7)was weighed and the sifted CSD from step 1 added, then dispersed by handand the mixture blended for 5 minutes in the blender from Step 3. Thisportion was labelled as Example 11. The mixture was compressed to formtablets.

Examples 10 and 11 were manufactured in a substantially similar mannerto Examples 9 and 10 with the following exceptions.

1. All ingredients were sifted through a 20 mesh sieve.

2. Drug and intragranular ingredients were blended for 10 minutes.

3. The amounts of water and SD3A alcohol were adjusted for thedifference in batch size.

4. Dried granule was milled using a Comil Model 197AS with 0.062"screen.

5. Example 11 was dried in a tray drier.

6. The magnesium stearate was blended for 10 minutes after 10 minutespreblend of the milled granule and other ingredients.

                                      TABLE 3    __________________________________________________________________________    Example         Compression               Hardness    Disintegration                                    Ejection Force                                           Stress Cracks    Numbers         Force (kN)               (kP) Friability (%)                           Time (mins)                                    (Newtons)                                           (after heading.sup.1)    __________________________________________________________________________    3a)  15.256               10.0 0.035  15.36    395    Yes    3b)  17.896               13.3 0.041  16.60    452    Yes    4    14.716               8.2.sup.3                    0.107  13.94    305    Yes.sup.2    5a)  15.343               9.9  0.15   17.95    300    Yes    5b)  17.956               12.5 0.10   19.96    329    Yes    6a)  15.058               11.9 0.15   18.04    306    Yes/faint    6b)  17.771               14.7 0.14   17.68    324    Yes    7a)  15.495               12.6 0.13   18.89    366    No    7b)  17.896               15.3 0.14   20.11    411    No    8a)  14.3  5.9  1.78   not available (N/A)                                    410    8b)  31.4  9.7  1.70   N/A      450    9a)  14.7  13.6 0.04   10.3     332    9b)  30.7  22.8 0.03   12.6     330    10   Setting 6               14.4        N/A      N/A    Yes    11   Setting 7               15.5        N/A      N/A    No    __________________________________________________________________________     .sup.1 Heated in a 50° C. forced air oven to simulate film coating     .sup.2 Stress cracks before and after heating.     .sup.3 One tablet broke in half (unacceptable hardness)

As can be seen from the results, the tablet of example 4 (which lackscolloidal silicon dioxide and has microcrystalline celluloseintragranularly broke in half during tumbling, to simulate film coatingconditions. The hardness of the tablet is therefore totallyunacceptable. On the contrary, when colloidal silicon dioxide was added(example 3) the tablet surprisingly did not break and furthermore thedisintegration time and ejection force increased by substantially lessthan would be expected.

The tablets of examples 5 and 6, like that of example 3, developedstress cracks after heating. In the tablet of example 3 there waspresent colloidal silicon dioxide and intragranular microcrystallinecellulose; in example 5 the microcrystalline cellulose was alsointragranular, but there was no colloidal silicon dioxide; and inexample 6 again there was no colloidal silicon dioxide, but themicrocrystalline cellulose was extragranular. Surprisingly, however,when colloidal silicon dioxide is present and the microcrystallinecellulose is extragranular, there appears to be synergy which preventsstress cracking. This effect can be seen in the tablet of example 7where there are no stress cracks, and furthermore the hardness andfriability were good. As with the tablet of example 3, thedisintegration and ejection force were increased substantially less thanwould be expected.

As can also be seen from comparative example 8a) the hardness value isvery low and the friability fails the US Pharmacopoeia (USP) limit of1%. Even at the very high compression force used in example 8b), thefriability still fails the USP test.

In contrast on the addition of about 0.1% w/w of colloidal silicondioxide (in example 9a and b), hardness and friability have dramaticallyimproved. Furthermore the ejection force, which was good before theaddition of colloidal silicon dioxide is still good, and in faceactually improved on its addition. The disintegration time of thetablets of example 9 is also very satisfactory.

Additionally when the formulation of example 11 is repeatedincorporating colloidal silicon dioxide in amounts ranging from 0.05 to3% w/w, excellent tablets can be consistently produced having a highhardness and low friability value, substantially free of stress-cracks.

The robust tablet formulation of the invention therefore canconsistently provide valaciclovir tablets having excellent handlingcharacteristics which are suitable for film coating and which still havean adequate lubricating and disintegration time.

We claim:
 1. A tablet comprising at least about 50% w/w valaciclovir ora salt thereof, a microcrystalline cellulose filler, a binding agent, alubricant selected from the group consisting of talc, sodium laurylsulphate and alkaline earth metal stearates and about 0.05 to about 3%w/w colloidal silicon dioxide wherein the valaciclovir or a salt thereofis present within the granules of the tablet, the lubricant, silicondioxide and at least a portion of the filler is present extragranularly;wherein the friability of the tablet does not exceed 1%, the hardness isat least 9 kP, and the ejection force does not exceed 1000 Newtons.
 2. Atablet as claimed in claim 1 wherein the colloidal silicon dioxide ispresent in an amount of about 0.1% to about 0.5% w/w.
 3. A tablet asclaimed in claim 1 wherein the filler is present in an amount of about3% w/w to about 30% w/w.
 4. A tablet as claimed in claim 3 wherein thefiller is present at about 5% to about 15% w/w.
 5. A tablet as claimedin claim 4, wherein the filler is present at about 10% w/w.
 6. A processfor preparing a tablet comprising at least about 50% w/w valaciclovir ora salt thereof, a binding agent, a lubricant selected from the groupconsisting of talc, sodium lauryl sulphate and alkaline earth metalstearate, about 0.05 to about 3% w/w colloidal silicon dioxide, andabout 3 to about 30% w/w or microcrystalline cellulose filler; whereinthe hardness of the tablet is at least 9 kPk, the friability is not morethan 1%, and the ejection force is not more than 1000 N; said processcomprising forming granules by mixing the valaciclovir or salt, optionalbinding agent or a portion thereof, and optionally a portion of filler;granulating with a granulating solution to form granules or dissolvingthe binding agent or a portion thereof in the granulating solutionbefore adding to valaciclovir; drying the granules; blending thegranules with the lubricant, colloidal silicon dioxide, and at least aportion of the filler; and then compressing the blended mixture to forma tablet.
 7. A tablet as claimed in claim 1, wherein the particle sizeof filler is about 20 to about 300 μm.
 8. A tablet as claimed in claim 1wherein the binding agent is present at about 1% to about 5% w/w.
 9. Atablet as claimed in claim 1 wherein the binding agent ismethylcellulose or povidone.
 10. A tablet as claimed in claim 9 whereinthe binding agent is povidone.
 11. A tablet as claimed in claim 10wherein the povidone is povidone K90 grade.
 12. A tablet as claimed inclaim 1 wherein the lubricant is present at about 0.1% to about 2.0%w/w.
 13. A tablet as claimed in claim 12 wherein the lubricant is analkaline earth metal stearate.
 14. A tablet as claimed in claim 13wherein the lubricant is magnesium stearate and is present at about 0.1%to about 1.0% w/w.
 15. A tablet as claimed in claim 1 wherein thevalaciclovir or its salt is present at about 65% to about 85% w/w.
 16. Atablet as claimed in claim 1 comprising valaciclovir hydrochloride. 17.A tablet as claimed in claim 16 wherein the valaciclovir hydrochlorideis anhydrous crystalline form including substantially a d spacingpattern as follows:d spacing pattern (in Angstroms):
 10. 20±0.08,8.10±0.06, 7.27±0.06, 6.08±0.05, 5.83±0.03, 5.37±0.02, 5.23±0.02,4.89±0.02, 4.42±0.02, 4.06±0.02, 3.71±0.02, 3.39±0.02, 3.32±0.02,2.91±0.02, 2.77±0.02.
 18. A tablet as claimed in claim 1 wherein thetapped bulk density of valaciclovir or salt thereof is about 0.1 toabout 0.9 g/cc.
 19. A tablet as claimed in claim 1 which furtherincludes a disintegrating agent present at about 0.05% to about 20% w/w.20. A tablet as claimed in claim 19 wherein the disintegrating agent isa non-ionic disintegrating agent.
 21. A tablet as claimed in claim 20wherein the disintegrating agent is crospovidone present at about 0.5%to about 7% w/w.
 22. A tablet comprising about 65% to about 85% w/wanhydrous crystalline valaciclovir hydrochloride including the d spacingdiffraction pattern of claim 17, about 0.5% to about 5% w/w of povidone,about 3% to about 30% w/w of a microcrystalline cellulose filler, about0.5 to about 7% w/w of a non-ionic disintegrating agent, about 0.1% toabout 1.0% of an alkaline earth metal stearate lubricant and about 0.1%to about 0.5% w/w of colloidal silicon dioxide, wherein the valaciclovirhydrochloride is present intragranularly; and wherein the filler,stearate lubricant and colloidal silicon dioxide are presentextragranularly.
 23. A tablet as claimed in claim 1 which is filmcoated.
 24. A tablet as claimed in claim 1 for use in medical therapy.25. A method of treatment of a herpes virus infection in a humancomprising administering to the host one or more tablets as claimed inclaim 1 to administer an effective anti-herpes viral amount ofvalaciclovir or a salt thereof.
 26. A process for preparing a tabletcomprising at least about 50% w/w valaciclovir or a salt thereof, abinding agent, a microcrystalline cellulose filler, a lubricant selectedfrom the group consisting of talc, sodium lauryl sulphate and alkalineearth metal stearate and about 0.05 to about 3.0% colloidal silicondioxide, wherein the friability of the tablet does not exceed 1%, thehardness is at least 9 kP and the ejection force does not exceed 10000N; said process having the valaciclovir or its salt present within thegranules of the tablet, and the lubricant, colloidal silicon dioxide,and at least a portion of the microcrystalline cellulose filler presentextragranularly.
 27. A process for preparing a tablet comprising atleast about 50% w/w valaciclovir or a salt thereof, a binding agent, amicrocrystalline cellulose filler, a lubricant selected from the groupconsisting of talc, sodium lauryl sulphate and alkaline earth metalstearate, and about 0.05 to 3.0% w/w colloidal silicon dioxide; whereinthe hardness of the tablet is at least 9 kP, the friability is not morethan 1%, and the ejection force is not more than 1000 N; said processcomprising forming granules which include valaciclovir or a salt thereofand then blending the lubricant, colloidal silicon dioxide and at leasta portion of the filler with said granules.
 28. A process according toclaim 26 comprising forming granules by mixing said valaciclovir orsalt, optionally a binding agent or a portion thereof, and optionally aportion of the filler; granulating with a granulating solution to formgranules or dissolving the binding agent or a portion in the granulatingsolution before adding to valaciclovir; drying the granules; blendingthe granules with the lubricant, colloidal silicon dioxide, and filleror a portion thereof; and then compressing the blended mixture to form atablet.